Human Cytomegalovirus (HCMV) is a major cause of congenital birth defects and causes severe disease in a wide variety of immunosuppressed patient populations, including hematological cancer patients and transplant recipients. We have found that HCMV institutes a pro-viral metabolic program that drives numerous cellular metabolic activities to support the production of viral progeny. Key aspects of this metabolic reprogramming include targeting the AMP-activated kinase (AMPK) and the calmodulin dependent-kinase kinase (CamKK), both of which we find are critical for successful HCMV infection. Further, our data indicate that the HCMV UL26 protein is an important viral metabolic determinant that activates fatty acid biosynthesis, a metabolic pathway essential for infection. Many questions remain about how these factors contribute to metabolic reprogramming and successful infection. To address these questions, we will pursue the following aims: 1) Elucidate how AMPK contributes to HCMV-mediated metabolic reprogramming; 2) Determine how calmodulin-dependent kinase kinase signaling contributes to HCMV infection; and, 3) Elucidate how the HCMV UL26 protein contributes to viral metabolic reprogramming. We expect the outcome of our research to be the identification of specific mechanisms through which HCMV manipulates metabolic regulation to support infection. The proposed work will broaden our understanding of an important host pathogen interaction, and given that these processes are essential for productive infection, the proposed experiments will highlight novel targets for therapeutic intervention.